We propose that Southern Illinois University Parkinson Disease Center participate in the design and performance of a large, multicenter clinical trial of neuroprotective agents in Parkinson disease. There are more than 500,000 people in the United States who are affected by Parkinson disease with 50,000 new cases each year. The annual cost is estimated to be 10 billion dollars per year [1]. Parkinson disease is an age-related disease and with the aging of the baby boom population, the number of people with Parkinson disease will increase substantially after the year 2010. Parkinson disease is characterized by a long preclinical phase, the onset of symptoms at about 60 years of age and progression to severe disability over about 10 to 25 years. The objective of the present project is to identify compounds that are safe and effective in retarding clinical progression in Parkinson disease. The specific aims of the project are to: (1) identify compounds that have potential as neuroprotective agents in Parkinson disease; (2) design clinical trials to test the effects of experimental compounds on the rate of progression of Parkinson disease; (3) conduct pilot studies of selected compounds to determine tolerance and safety of their use in man; and, (4) conduct a large, multicenter clinical trial to determine if selected compounds retard the rate of progression in Parkinson disease. The final design of the pilot studies and large, multicenter clinical trial will be developed collaboratively by the Steering and Oversight Committees, the Coordinating Center and Statistical Center, and the NINDS Scientific Program Director for the project. The following suggestions are proposed regarding the study design: (1) to include the study of estrogen as a potential neuroprotective agent in Parkinson disease; (2) to stratify the study population on the basis of rural vs. urban residence; (3) to use cognitive impairment as one of the measures of the progression of Parkinson disease; (5) to study the pharmacogenomics of the selected compounds studied in the large clinical trial; and, (6) to include a brain autopsy study to confirm the diagnosis and a neuropathology study of the effects of the selected compounds tested on the pathological changes in Parkinson disease. It is proposed that the Autopsy/Neuropathology Program at Southern Illinois University serve as the central resource for a brain autopsy and neuropathology study if it is included in the final study design.